scholarly journals Oleacein Attenuates the Pathogenesis of Experimental Autoimmune Encephalomyelitis through Both Antioxidant and Anti-Inflammatory Effects

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1161
Author(s):  
Beatriz Gutiérrez-Miranda ◽  
Isabel Gallardo ◽  
Eleni Melliou ◽  
Isabel Cabero ◽  
Yolanda Álvarez ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Proinflammatory Cytokines ◽  
Histological Evaluation ◽  
Autoimmune Encephalomyelitis ◽  
Bv2 Cells ◽  
Bv2 Microglia ◽  
Anti Inflammatory ◽  
The Impact ◽  
Experimental Autoimmune

Oxidative stress and proinflammatory cytokines are factors affecting multiple sclerosis (MS) disease progression. Oleacein (OLE), an olive secoiridoid, possesses powerful antioxidant and anti-inflammatory activities, which suggests its potential application to treat neuroinflammatory disorders. Herein, we investigated the impact of OLE on the main clinic-pathological features of experimental autoimmune encephalomyelitis (EAE), an animal model for MS, including paralysis, demyelination, central nervous system (CNS) inflammation/oxidative stress and blood-brain barrier (BBB) breakdown. Methods: Mice were immunized with the myelin oligodendrocyte glycoprotein peptide, MOG35-55, to induce EAE, and OLE was administrated from immunization day. Serum, optic nerve, spinal cord and cerebellum were collected to evaluate immunomodulatory activities at a systemic level, as well as within the CNS. Additionally, BV2 microglia and the retinal ganglion cell line RGC-5 were used to confirm the direct effect of OLE on CNS-resident cells. Results: We show that OLE treatment effectively reduced clinical score and histological signs typical of EAE. Histological evaluation confirmed a decrease in leukocyte infiltration, demyelination, BBB disruption and superoxide anion accumulation in CNS tissues of OLE-treated EAE mice compared to untreated ones. OLE significantly decreased expression of proinflammatory cytokines (IL-13, TNFα, GM-CSF, MCP-1 and IL-1β), while it increased the anti-inflammatory cytokine IL-10. Serum levels of anti-MOG35-55 antibodies were also lower in OLE-treated EAE mice. Further, OLE significantly diminished the presence of oxidative system parameters, while upregulated the ROS disruptor, Sestrin-3. Mechanistically, OLE prevented NLRP3 expression, phosphorylation of p65-NF-κB and reduced the synthesis of proinflammatory mediators induced by relevant inflammatory stimuli in BV2 cells. OLE did not affect viability or the phagocytic capabilities of BV2 microglia. In addition, apoptosis of RGC-5 induced by oxidative stressors was also prevented by OLE. Conclusion: Altogether, our results show that the antioxidant and anti-inflammatory OLE has neuroprotective effects in the CNS of EAE mice, pointing out this natural product as a candidate to consider for research on MS treatments.

scholarly journals Microglial Nox2 Plays a Key Role in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Chih-Fen Hu ◽  
San-Pin Wu ◽  
Gu-Jiun Lin ◽  
Chi-Chang Shieh ◽  
Chih-Sin Hsu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Lupus Erythematosus ◽  
Autoimmune Encephalomyelitis ◽  
Chemokine Production ◽  
Phagocyte Nadph Oxidase ◽  
Cytokines And Chemokines ◽  
Gene Ablation ◽  
The Impact ◽  
Experimental Autoimmune

While oxidative stress has been linked to multiple sclerosis (MS), the role of superoxide-producing phagocyte NADPH oxidase (Nox2) in central nervous system (CNS) pathogenesis remains unclear. This study investigates the impact of Nox2 gene ablation on pro- and anti-inflammatory cytokine and chemokine production in a mouse experimental autoimmune encephalomyelitis (EAE) model. Nox2 deficiency attenuates EAE-induced neural damage and reduces disease severity, pathogenic immune cells infiltration, demyelination, and oxidative stress in the CNS. The number of autoreactive T cells, myeloid cells, and activated microglia, as well as the production of cytokines and chemokines, including GM-CSF, IFNγ, TNFα, IL-6, IL-10, IL-17A, CCL2, CCL5, and CXCL10, were much lower in the Nox2−/− CNS tissues but remained unaltered in the peripheral lymphoid organs. RNA-seq profiling of microglial transcriptome identified a panel of Nox2 dependent proinflammatory genes: Pf4, Tnfrsf9, Tnfsf12, Tnfsf13, Ccl7, Cxcl3, and Cxcl9. Furthermore, gene ontology and pathway enrichment analyses revealed that microglial Nox2 plays a regulatory role in multiple pathways known to be important for MS/EAE pathogenesis, including STAT3, glutathione, leukotriene biosynthesis, IL-8, HMGB1, NRF2, systemic lupus erythematosus in B cells, and T cell exhaustion signaling. Taken together, our results provide new insights into the critical functions performed by microglial Nox2 during the EAE pathogenesis, suggesting that Nox2 inhibition may represent an important therapeutic target for MS.

scholarly journals Lowering blood cholesterol does not affect neuroinflammation in experimental autoimmune encephalomyelitis

2021 ◽  
Author(s):  
solenne vigne ◽  
Donovan Duc ◽  
Yannick Yersin ◽  
Jessica Rebeaud ◽  
Florian Ruiz ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Cholesterol Level ◽  
Blood Cholesterol ◽  
Lipid Lowering ◽  
Blood Levels ◽  
Disease Course ◽  
Blood Cholesterol Level ◽  
Autoimmune Encephalomyelitis ◽  
The Impact ◽  
Experimental Autoimmune

Abstract Background: Multiple sclerosis (MS) is a chronic disabling disease of the central nervous system (CNS) commonly affecting young adults. There is increasing evidence that environmental factors are important in the development and course of MS. Metabolic syndrome (MetS) including dyslipidemia has been associated with a worse outcome in MS disease. Furthermore, the lipid lowering drugs statins have been proposed to improve MS disease course. However, cholesterol is also rate-limiting for myelin biogenesis and promotes remyelination in MS animal models. Thus, the impact of circulating blood cholesterol level during the disease remains debated and controversial. Methods: We assessed the role of circulating cholesterol on the murine model of MS, the experimental autoimmune encephalomyelitis (EAE) disease using two different approaches: 1) the mouse model of familial hypercholesterolemia induced by low density lipoprotein receptor (LDLr) deficiency, and 2) the use of the monoclonal anti-PCSK9 neutralizing antibody alirocumab which reduces LDLr degradation and consequently lowers blood levels of cholesterol. Results: Elevated blood cholesterol levels induced by LDLr deficiency did not worsen clinical symptoms of mice during EAE. In addition, we observed that the anti-PCSK9 antibody alirocumab did not influence EAE disease course, nor modulate the immune response in EAE. Conclusions: These findings suggest that blood cholesterol level has no direct role in neuro-inflammatory diseases and that the previously shown protective effects of statins in MS are not related to circulating cholesterol.

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